J. Org. Chem. 1983,48,3105-3106 librium and the AG (at 25 "C) decreased from 95% (AG = 1.745 kcal/mol) to 86% (AG = 1.028 kcal/mol) to 55% (AG = 0.119 kcal/mol). This result is due to the ability of dimethyl sulfoxide to compete with a carbonyl group for the NH hydrogen bond. In addition, dimethyl sulfoxide may associate with the carbonyl group.% Acetone shows less ability to break the NH-0 hydrogen bond in the cis isomer because the carbonyl group in acetone is not as polarized as the sulfoxide group in dimethyl sulfoxide. The results of these studies are consistent with the effect of solvents on the proportions of cis and trans isomers of the Schiff bases of monoalkylamines and ethyl acetoacetate where the cis/trans ratio varies from 151in CC14to 1 0 1 in CDCl, to 7:5 in Me2S0.lg The activation energy for isomerization (13.6 kcal/mol) in Me2S0 is consistent with either a mechanism involving isomerization about the double bond or a mechanism involving a ketimine intermediate. Rotation barriers as low as 9.1 kcal/mol have been observed for dialkenylamino ketones.% This low rotation barrier is apparently due to the fact that the transition state for isomerization resembles one of the possible charge-separated resonance structures. In order to test whether a ketimine was present, we measured the exchange of the olefin hydrogen atom of I in Me2SO/D20. This hydrogen atom did exchange but at a much slower rate than isomerization, ruling out a mechanism involving only isomerization via the ketimine. In conclusion, this paper illustrates another example of a useful approach to the analysis of conformationally (configurationally)mobile systems. This approach involves initial crystallographic analysis and subsequent solution studies. When information from these studies (crystallographic and solution) is combined, a complete picture of conformationally mobile systems is obtained.
Acknowledgment. This research was supported by NIH Grant ES-00929 for which we are grateful. Registry No. Ia, 21759-74-0; Ib, 21731-13-5. Supplementary Material Available: Table 11, final temperature factors; Table 111, bond lengths; Table IV,bond angles; Table V, intermolecular contacts (3 pages). Ordering information is given on any current masthead page. (24) Y. Shvo and H. Shanan-Atidi,J. Am. C h m . SOC.,91,6684 (1969). (25) The X-Ray System (Version of June 1972, Update April 1974, Technical Report TR-192 of the Computer Science Center, Univerity of Maryland, June 1972) WBB used for all crystallographic computations reported.
4-Alkoxybenzonitriles from 0 -Alkyl-4-nitrobenzaldoximes: An Elimination-Aromatic Substitution Reaction David Madeb,* Ricardo Granados, and Cristina Minguill6n Department of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain Received October 27, 1982
3105
Scheme I
r
HCZNOR
1 FN
1
1
CN
FN
a. R=CH3
and oximate anion^.^ The latter nucleophile reacts with 4-nitrobenzonitrile to give an 0-aryl aldoxime that undergoes elimination to the corresponding nitrile: these transformations constitute a "one pot" method for the conversion of aldoximes into nitrile^.^ In an extension of this (E)-4-nitrobenzaldoxime was found to give 4-hydroxybenzonitrile upon alkaline treatment in Me2S0 solution containing a small amount of 4-nitrobenzonitrile. The proposed reaction pathway5 involves a nitro displacement to afford 0-(4-cyanophenyl)-4-nitrobenzaldoxime, followed by a base-promoted elimination leading to 4-hydroxybenzonitrile(the leaving group) and the chain carrier, 4-nitrobenzonitrile. In relation to the above results, we now report that in dipolar aprotic solvents (dimethylformamide or dimethyl sulfoxide),the 0-alkyl ethers of 4-nitrobenzaldoxime react with bases to give the corresponding 4-alkoxybenzonitriles in good yields. The starting oxime ethers la-d were obtained in excellent yields by alkylation of 4-nitrobenzaldoximesodium salt with the appropriate alkyl halide in DMF solution.6 Treatment of a DMF solution of the above oxime ethers with an excess of sodium hydride at room temperature afforded the 4-alkoxybenzonitriles 2a-d, which were identified by their melting points and spectroscopic characteristics. Thus, the IR spectra of 2a-d showed a strong absorption at 2235 cm-', due to the cyano group stretching. Comparison of the NMR spectra of 2a-d with those of the oxime ethers l a 4 showed the disappearance of the aldoxime proton signal near 6 8.0 and an upfield shift of 0.6-0.8 ppm for the aromatic signals. Mass spectrometry was used to confirm the structure of 2b. The above elimination-aromatic substitution reactions were also carried out in an NMFt tube with hexadeuterated Me2S0 as a solvent; similar results were then obtained. 2a-c were formed very fast (less than 1 min after the addition of NaH) whereas in the case of 2d the reaction was completed after 3 h. Unfortunately, the reaction kinetics could not be established, since the hydrogen evolved during the process caused a loss of resolution of the NMR signals. We propose a reaction pathway for the formation of 4-alkoxybenzonitriles2a-d involving an intial elimination of the alkoxide moiety from the oxime ethers la-d, followed by a displacement of the nitro group (as nitrite anion) by the nucleophilic attack of the alkoxide anion (Scheme I). The second step takes place readily because of the activating effect of the dipolar aprotic solvent. The replacement of the nitro group on 4-nitrobenzophenone by
It has been reported that, in dipolar aprotic solvents, an aromatic nitro group activated by a single ortho or para carbonyl-type function can be replaced by nucleophiles ranging from hydroxyl or alkoxy1anions' to m e r ~ a p t i d e s ~ ? ~ (3) Beck, J. R. J . Org. Chem. 1973, 38, 4086. (1) Gorvin, J. H. Chem. Znd. (London) 1967, 1525. (2) Beck, J. R. J. Org. Chem. 1972, 37, 3224.
(4) Knudsen, R. D.; Snyder, H. R. J . Org. Chem. 1974,39, 3343. (5) Knudsen, R. D.; Morrice, A. G.; Snyder, H. R. J . Org. Chem. 1975,
40, 2878.
(6) Leclerc, G.; Bieth, N.; Schwartz, J. J . Med. Chem. 1980, 23, 620.
0022-3263/83/1948-3105$01.50/00 1983 American Chemical Society
J. Org. Chem. 1983,48, 3106-3108
3106
sodium methoxide does not occur in dioxane.' Moreover, alkaline treatment of alkyl and aryl ethers of 4-nitrobenzaldoxime in water-dioxane solution leads to 4-nitrobenzonitrile, without a trace of nitro substitution.' The alkylation of the oxime and the elimination-substitution reactions can be carried out in a single operation, synthetically useful for the preparation of 4-alkoxybenzonitriles from 4-nitrobenzaldehyde. Thus, treatment of 4-nitrobenzaldoximewith benzyl bromide (1equiv) and NaH (3 equiv) in DMF at room temperature afforded the nitrile 2c in good yields. However, the method has some limitations; thus, reaction of 4-nitrobeddoxime with the tertiary alkyl halide ethyl 2-bromo-2-methylpropionatedid not afford the expected ethyl 2-(4-cyanophenyl)-2methylpropionate but instead formed 4-ethoxybenzonitrile (2e, 68% yield). This compound can arise from nitro substitution by sodium ethoxide, probably formed in the autocondensation of the initial intermediate, sodium 2(ethoxycarbonyl)-2-methylethoxide.
Experimental Section NMR spectra were determined on a Perkin-Elmer R-24B (60 MHz) instrument by using internal Me4% as a reference. IR spectra were recorded on a Perkin-Elmer 577 spectrophotometer. Melting points were determined in a Buchi apparatus and are uncorrected. The mass spectrum was determined on a Hewlett-Packard 5930A mass spectrometer. Microanalyses were performed by Instituto de Quimica Bio-Orghica, Barcelona. Alkylation of 4-Nitrobenzaldoxime. To a suspension of 0.24 g (10 mmol) of sodium hydride (dispersion in oil, washed with hexane) in 25 mL of anhydrous DMF was added 1.66 g (10 "01) of 4-nitrobenzaldoxime portionwise. The dark red solution was stirred at room temperature for 10 min, and a solution of 10 mmol of the alkylating agent (methyl iodide, epichlorohydrin, benzyl bromide or 2-butyl bromide, respectively, for la-d) in 5 mL of anhydrous DMF was added dropwise. The mixture was stirred for 30 min, poured into 150 mL of water, and extracted with ether. The organic extracts were washed with water, dried, and evaporated to give the ethers la-d, which were purified by vacuum distillation. 0-Methyl-4-nitrobenzaldoxime (la): yield 89%; NMR (CDC13-CC14) 6 3.93 ( 8 , 3 H, OCH3),7.57 (d, J = 8 Hz, 2 H, H2v6),7.91 (8, 1H, CH=N), 8.07 (d, J = 8 Hz, 2 H, H3"). Anal. Calcd for C8H8N203:C, 53.33; H, 4.48; N, 15.55. Found C, 53.57; H, 4.31; N, 15.72. O-(2,3-Epoxypropyl)-4-nitrobenzaldoxime (lb): yield 90%; NMR (CDC13)6 2.6-3.0 (AB part of an ABX, 2 H, CH2oxirane), 3.1-3.4 (m, 1H, CH oxirane), 3.9-4.6 (AB part of an ABX, 2 H, OCH2),7.65 (d, J = 7.5 Hz, 2 H, H2% 8.08 ( 8 , 1 H, CH=N), 8.14 (d, J = 7.5 Hz, 2 H, H3*5).Anal. Calcd for Cl&&JZO4: C, 54.05; H, 4.54; N, 12.61. Found: C, 53.90, H, 4.59; N, 12.87. 0-Benzyl-4-nitrobenzaldoxime (IC): yield 86%; NMR (CDC13) 6 5.13 (8, 2 H, CHZ), 7.25 (8, 5 H, C6H5), 7.56 (d, J = 8 Hz, 2 H, H2p6), 8.00 ( 8 , 1 H, CH=N), 8.07 (d, J = 8 Hz, 2 H, H3v5). Anal. Calcd for C14HlZN203:C, 65.62; H, 4.72; N, 10.93. Found: C, 65.74; H, 4.59; N, 11.01. 0-(2-Buty1)-4-nitrobenzaldoxime (ld): yield 91%; NMR (CC14)6 0.94 (t,3 H, CHZCH,), 1.25 (d, 3 H, CHCH3),1.3-1.8 (m, 2 H, CH,), 4.15 (m, 1H, OCH), 7.56 (d, J = 8 Hz, 2 H, H2s6),7.99 (s, 1 H, CH=N), 8.05 (d, J = 8 Hz, 2 H, H3,5). Anal. Calcd for CllH14N203:C, 59.45; H, 6.35; N, 12.61. Found: C, 59.65; H, 6.47; N, 12.64. 4-Alkoxybenzonitriles 2a-d. A solution of 5 mmol of the appropriate oxime ether 1 in 10 mL of anhydrous DMF was added to a suspension of 8 "01 of NaH in 20 mL of DMF. The mixture was stirred at room temperature for 1 h (4 h in the case of la). The workup was carried out as above. 4-Methoxybenzonitrile (2a): yield 92%; mp 57-59 "C (litasmp 58-59 "C); IR (CHC13) 2235 cm-I (CN); NMR (CC14)6 3.77 (s,3 H, OCH3),6.80 (d, J = 9 Hz, 2 H, H3v6),7.39 (d, J = 9 Hz, 2 H, H2s6). 4-(2,3-Epoxypropoxy)benzonitrile (2b): yield 82%; mp 64-66 "C (lit9mp (7)
Hegarty, A. F.; Tuohey, P. J. J. Chem. SOC.,Perkin Trans. 2 1980,
67 "C); IR (CHCl,) 2235 cm-I (CN); NMR (CC14)6 2.5-2.9 (AB part of an ABX, 2 H, CH, oxirane), 3.0-3.3 (m, 1H, CH oxirane), 3.7-4.4 (AB part of an ABX, 2 H, OCH,), 6.86 (d, J = 7.5 Hz, 2 H, H3*5),7.46 (d, J = 7.5 Hz, 2 H, H2,6);mass spectrum, m / e (relative intensity) 175 (74, M+), 119 (91, McLafferty rearrangement), 57 (100, oxiranylmethyl cation). 4-(Benzyloxy)benzonitrile (2c): yield 87%; mp 91-93 "C (lit.8mp 94 "C); IR (CHC13)2235 cm-' (CN); NMR (CDC13)6 4.99 (8, 2 H, CHz),6.85 (d, J = 8 Hz, 2 H, H3*5),7.25 (s, 5 H, CsH5), 7.40 (d, J = 8 Hz, 2 H, H2s6). 4-(2-Butoxy)benzonitrile(2d): yield 89%; bp 120 "C (1mmHg) [lit.lobp 104-111"C (1.3 mmHg)]; IR (NaCl) 2235 cm-' (CN); NMR (CC14)6 0.95 (t, 3 H, CH,CH3), 1.26 (d, 3 H, CHCH3), 1.4-1.9 (m, 2 H, CH,), 4.22 (m, 1H, OCH), 6.73 (d, J = 8 Hz, 2 H, H3v5),7.46 (d, J = 8 Hz, 2 H, H2s6). Direct Synthesis of 2c from 4-Nitrobenzaldoxime. Over a suspension of 30 mmol of NaH in 25 mL of anhydrous DMF was added 10 mmol of the oxime portionwise. The mixture was stirred at room temperature for 10 min, and then 10 mmol of benzyl bromide in 5 mL of DMF was added dropwise. After 30 min of stirring and the usual workup, nitrile 2c was isolated in 85% yield. Registry No. 1 (R = H), 1129-37-9; la, 33499-32-0; lb, 86120-18-5; IC, 86120-19-6; Id, 86120-20-9; 2a, 874-90-8; 2b, 38791-92-3; 2c, 52805-36-4; 2d, 86120-21-0; 2e, 25117-74-2;ethyl 2-bromo-2-methylpropionate,600-00-0; methyl iodide, 74-88-4; epichlorohydrin, 106-89-8; benzyl bromide, 100-39-0; 2-butyl bromide, 78-76-2. (10)Cooper, F. C.; Partridge, M. W. J. Chem. SOC.1953, 255.
Use of Phosphorus Pentoxide: Esterification of Organic Acidst Amalendu Banerjee,* Saumitra Sengupta, Mohini Mohan Adak, and Gopal Chandra Banerjee
Chemistry Department, Jadavpur University, Calcutta 700 032, India Received August 11, 1982
With a view to developing a method of esterification at room temperature on a vertical column, we chose phosphorus pentoxide as the packing reagent, which was diluted with anhydrous copper sulfate and sodium sulfate to avoid the blocking of the column. Anhydrous copper sulfate served as a water scavenger and also as an indicator for the progress of the reaction and the duration of the reactivity of the column through its color change, while anhydrous sodium sulfate retained the desired porosity and was useful for the sustained activity of the column with its water-absorbing property. Phosphorus pentoxide has been frequently used in diverse types of organic reactions, but surprisingly only one example of its use in esterification reaction has been reported.' Coupled with this fact, this solid acidic oxide, possessing an extraordinary dehydrating capacity, made itself a unique material of choice for the present investigation. Thus, several primary aliphatic carboxylic acids were converted into the corresponding ethyl esters in varying yields (see the Experimental Section). A striking feature of this method was that aromatic acids could be recovered unchanged. But the process was slow; moreover, there was sufficient indication through arresting the acid-catalyzed reaction that it occurred partly (20-25 %) on the column and partly (4040%) during the removal of the excess alcohol from the steam bath. Therefore, the reaction was studied at room temperature for varying time
1313.
(8) Vowinkel, E.; Bartel, J. Chem. Ber. 1974, 107, 1221. (9) Petrow, V.; Stephenson, 0. J. Pharm. Pharmacol. 1963, 5, 359.
'Taken in part from the Ph.D. Dissertation of G.C.B.
0022-326318311948-3106$01.50/0 0 1983 American Chemical Society
